1. Field of the Invention
This invention relates to methods and apparatus for performing microanalytic and microsynthetic analyses and procedures. In particular, the invention relates to microminiaturization of genetic, biochemical and chemical processes related to analysis, synthesis and purification. Specifically, the invention provides a microsystem platform and a micromanipulation device to manipulate the platform by rotation, thereby utilizing the centripetal forces resulting from rotation of the platform to motivate fluid movement through microchannels embedded in the microplatform. The microsystem platforms of the invention are also provided optionally having system informatics and data acquisition, analysis and storage and retrieval informatics encoded on the surface of the disk opposite to the surface containing the fluidic components. Methods for performing any of a wide variety of microanalytical or microsynthetic processes using the microsystems apparatus of the invention are also provided.
2. Background of the Related Art
In the field of medical, biological and chemical assays, a mechanical and automated fluid handling systems and instruments produced to operate on a macroscopic (i.e., milliliters and milligrams) scale are known in the prior art.
U.S. Pat. No. 4,279,862, issued Jul. 21, 1981 to Bertaudiere et al. disclose a centrifulgal photometric analyzer.
U.S. Pat. No. 4,381,291, issued Apr. 26, 1983 to Ekins teach analytic measurement of free ligands.
U.S. Pat. No. 4,515,889, issued May 7, 1985 to Klose et al. teach automated mixing and incubating reagents to perform analytical determinations.
U.S. Pat. No. 4,676,952, issued Jun. 30, 1987 to Edelmann et al. teach a photometric analysis apparatus.
U.S. Pat. No. 4,745,072, issued May 17, 1988 to Ekins discloses immunoassay in biological fluids.
U.S. Pat. No. 5,160,702 issued Nov. 3, 1992 to Kopf-Sill et al. discloses a centrifuge rotor for analyzing solids in a liquid.
U.S. Pat. No. 5,171,695, issued Dec. 15, 1992 to Ekins discloses determination of analyte concentration using two labeling markers.
U.S. Pat. No. 5,173,262 issued Dec. 22, 1996 to Burtis et al. discloses a centrifuge rotor for processing liquids.
U.S. Pat. No. 5,242,803, issued Sep. 7, 1993 to Burtis et al. disclose a rotor assembly for carrying out an assay.
U.S. Pat. No. 5,409,665, issued Apr. 25, 1995 to Burd disclose cuvette filling in a centrifuge rotor.
U.S. Pat. No. 5,413,732, issued May 9, 1995 to Buhl et al. teach preparation of lyophilized reagent spheres for use in automated centrifugal blood analyzers.
U.S. Pat. No. 5,432,009, issued Jul. 11, 1995 to Ekins discloses a method for analyzing analytes in a liquid.
U.S. Pat. No. 5,472,603 issued Dec. 5, 1995 to Schembri discloses an analytical rotor for performing fluid separations.
Anderson, 1968, Anal. Biochem. 28: 545-562 teach a multiple cuvette rotor for cell fractionation.
Renoe et al., Clin. Chem. 20: 955-960 teach a "minidisc" module for a centrifulgal analyzer.
Burtis et al., Clin. Chem. 20: 932-941 teach a method for dynamic introduction of liquids into a centrifugal analyzer.
Fritsche et al. 1975, Clin. Biochem. 8: 240-246 teach enzymatic analysis of blood sugar levels using a centrifugal analyzer.
Burtis et al., Clin. Chem. 21: 1225-1233 a multipurpose optical system for use with a centrifugal analyzer.
Hadjiioannou et al. 1976, Clin. Chem. 22: 802-805 teach automated enzymatic ethanol determination in biological fluids using a miniature centrifugal analyzer.
Lee et al., 1978, Clin. Chem. 24: 1361-1365 teach an automated blood fractionation system.
Cho et al., 1982, Clin. Chem. 28: 1961-1965 teach a multichannel electrochemical centrifugal analyzer.
Bertrand et al., 1982, Clinica Chimica Acta 119: 275-284 teach automated determination of serum 5'-nucleotidase using a centrifugal analyzer.
Schembri et al., 1992, Clin. Chem. 3: 1665-1670 teach a portable whole blood analyzer.
Walters et al., 1995, Basic Medical Laboratory Technologies, 3.sup.rd ed., Delmar Publishers: Boston teach a variety of automated medical laboratory analytic techniques.
Recently, microanalytical devices for performing select reaction pathways have been developed.
U.S. Pat. No. 5,006,749, issued Apr. 9, 1991 to White disclose methods and apparatus for using ultrasonic energy to move microminiature elements.
U.S. Pat. No. 5,252,294, issued Oct. 12, 1993 to Kroy et al. teach a micromechanical structure for performing certain chemical microanalyses.
U.S. Pat. No. 5,304,487, issued Apr. 19, 1994 to Wilding et al. teach fluid handling on microscale analytical devices.
U.S. Pat. No. 5,368,704 issued Nov. 29, 1994 to Madou et al. teach microelectrochemical valves.
International Application, Publication No. WO93/22053, published Nov. 11, 1993 to University of Pennsylvania disclose microfabricated detection structures.
International Application, Publication No. WO93/22058, published Nov. 11, 1993 to University of Pennsylvania disclose microfabricated structures for performing polynucleotide amplification.
Columbus et al., 1987, Clin. Chem. 33: 1531-1537 teach fluid management of biological fluids.
Ekins et al., 1992, Ann. Biol. Clin. 50: 337-353 teach a multianalytical microspot immunoassay.
Wilding et al., 1994, Clin. Chem. 40: 43-47 disclose manipulation of fluids on straight channels micromachined into silicon.
The prior art discloses synthetic microchips for performing microanalytic and microsynthetic methods. One drawback in the prior art microanalytical methods and apparati has been the difficulty in designing systems for moving fluids on the microchips through channels and reservoirs having diameters in the 10-100 .mu.m range. Also, the devices disclosed in the prior art have required separate data analysis and storage media to be integrated into an instrument for performing the microanalysis, thereby unnecessarily increasing the complexity of the instruments designed to use the microchips, without a concomitant increase in the flexibility or usefulness of these machines.
There remains a need for a simple, flexible, reliable, rapid and economical microanalytic and microsynthetic reaction platform for performing biological, biochemical and chemical analyses and syntheses that can move fluids within the structural components of a microsystems platform. Such a platform should be able to move nanoliter to microliter amounts of fluid, including reagents and reactants, at rapid rates to effect the proper mixing of reaction components, removal of reaction side products, and isolation of desired reaction products and intermediates. There is also a need for an instrument for manipulating the microsystem platform to effect fluid movement, thermal control, reagent mixing, reactant detection, data acquisition, data analysis and data and systems interface with a user. Such devices are needed, in alternative embodiments, that are sophisticated (for professional, e.g., hospital, use), easy to use (for consumer, e.g., at-home monitoring, uses) and portable (for field, e.g., environmental testing, use). Such devices also advantageously combine "wet" chemistry capabilities with information processing, storing and manipulating ability.